EXPERT COMMENTARY

Vivian Fonseca, MD, on EMPA-REG OUTCOME: Empagliflozin Cuts CV Deaths

The EMPA-REG OUTCOME trial with the SGLT2 inhibitor, empagliflozin, was recently presented and published.1 It represents a landmark event in clinical trials for patients with type 2 diabetes.

In this trial, the investigators took very–high-risk patients with known cardiovascular disease and type 2 diabetes. More than 90% of patients had a prior acute coronary syndrome (ACS) event, putting them at very high risk for the development and hospitalization for heart failure, as well as increased mortality. Indeed, mortality and events in this trial were higher than in many other recent diabetes and cardiovascular disease trials.

The results are quite striking. There was a significant reduction in cardiovascular and all-cause mortality, as well as a significant 35% reduction in hospitalization for heart failure. (Figures 1 and 2.) This dramatically contrasts with other clinical trials, not only those testing glucose lowering, but also those on individual drug therapy for diabetes. Not only is the effect quite striking, it started very early, possibly within 3 to 6 months of starting the therapy. However, these were either components of the primary endpoint or secondary endpoints in the trial. The primary endpoint was a composite of myocardial infarction, stroke, and cardiovascular death. (Figure 3.) This was barely significant when the two empagliflozin groups were pooled together and compared with placebo. But individual empagliflozin doses of 10 mg and 25 mg did not meet statistical significance compared to

placebo. This is a very important limitation of the results of this trial, and it is shown only in the supplementary index. Importantly, myocardial infarction was not reduced, and stroke was slightly increased, although this was not statistically significant. Thus, the major impact of the drug appears to be on reducing the severity and progression of heart failure. This may clearly be due to its diuretic-like

effect, which is not surprising as a benefit in patients with heart failure. Interestingly, this effect appears to be independent and additive to other diuretics and treatments for heart failure, representing a novel approach to treating heart failure, possibly even beyond people with type 2 diabetes.

The results of this trial need to be contrasted with those of other diabetes drugs. Notably, recent incretin-related drugs have had no impact on cardiovascular events, and there is a question about the possible increase in hospitalization for heart failure with DPP-4 inhibitors.2-5 Also, pioglitazone is associated with an increase in the development of heart failure, although that did not lead to an increase in mortality and, remarkably, significantly reduced the development of heart attacks and strokes.6 Thus, there are important differences between the various therapies that we have for diabetes and the impact on the range of cardiovascular events. Clinicians must choose the most appropriate therapy based on the cardiovascular profile of the individual patient.

The underlying mechanisms for the benefits seen were not investigated in the trial and are unclear, but clearly, a diuretic effect may be important, as discussed above. If that is so, then this is likely to be a class effect since the very mechanism of action of SGLT2 inhibitors is to increase glycosuria and thereby cause an osmotic diuresis, with loss of significant amounts of fluid and possibly sodium. The lack of effect on other cardiovascular events needs further investigation because this was seen despite a significant drop in both glucose and blood pressure, and may relate to the otherwise optimal treatment of risk factors for this condition, including lipid-lowering therapy. It is well known that SGLT2 inhibitors increase LDL-C, and any such increase may dampen potential beneficial effects.

Will diabetes guidelines change as a result of this trial? This is very possible, particularly in relation to further opportunities to individualize therapy in relation to underlying heart disease profile. However, unless strongly confirmed by other trials, it is unlikely that empagliflozin will displace metformin as first-line therapy for patients, other than those with heart failure or following an ACS event.

Empagliflozin is not FDA approved for the treatment of cardiovascular disease (primary or secondary prevention) or heart failure in the United States.

Click on figures to view larger. All slides available for download in the Slide Library.

About the commentary authorVivian A. Fonseca, MD, is a Professor of Medicine in the Division of Endocrinology and Chief of the Section of endocrinology at Tulane University Medical Center in New Orleans, Louisiana.

Pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual package inserts for use outside of the United States.

September 2015

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